Cocaine and heroin dependence pose disproportionate public health, social, and economic problems via increased risk of medical and psychiatric morbidities, crime, and poor treatment outcome. Human laboratory studies have not examined choice of cocaine or cocaine/opioid combinations, nor interventions to reduce their use. In cocaine/heroin-dependent patients, a dual agonist-replacement approach for cocaine abuse using sustained release d-amphetamine (SR-AMP) with methadone has been shown safe and effective. However, combining the partial mu-opioid agonist buprenorphine (BLIP) rather than methadone with SR-AMP may have four advantages: (1) it is an alternative medication option that may be equally effective, (2) likely safer, (3) preferred by patients, and (4) more widely available. In this 3-year project, cocaine/heroin dependent volunteers will be studied to address two aims: Aim 1 (SR-AMP blockade of cocaine choice in non-treatment seekers). Study 1 will use a within-subject design to test the hypotheses that, relative to placebo SR-AMP (week 1), escalating-dose maintenance on SR-AMP 15 mg BID (week 2) then 30 mg BID (week 3) with BUP (8 mg/day in weeks 1-3) will: [1a] be safe and well tolerated; [1b] decrease choice of cocaine alone or combined with hydromorphone (HYD), relative to HYD alone and placebo on a choice progressive ratio schedule (4 conditions; randomized crossover, double blind, double dummy); [1c] attenuate subjective (high, liking) and physiological (HR, BP) effects during cocaine sampling before choice opportunities; and [1d] increase demand elasticity for cocaine. Aim 2 (SR-AMP prevention of cocaine relapse in treatment seekers). Study 2 will discharge BUP-maintained, illicit drug-abstinent volunteers from an inpatient unit, using a parallel-group, randomized (with stratification), double blind, placebo-controlled design to test the hypothesis that SR-AMP (likely 30 mg BID, based on Study 1 results) with cognitive behavioral therapy and voucher based reinforcement of protocol adherence will: [2a] prevent relapse to cocaine use during a 4-week outpatient evaluation period); [2b] improve medication adherence (number of days on which SR-AMP/BUP is consumed); [2c] attenuate cocaine withdrawal symptoms; and [2d] reduce number of days engaged in HIV risk behaviors. The innovative aims, rigorous methods and clinical/public health significance of this project (i.e. whether SR-AMP has potential efficacy for reducing cocaine use) is highly concordant with this RFA. [unreadable] [unreadable] [unreadable]